[show abstract][hide abstract] ABSTRACT: The reinforcing effects of cocaine are mediated by the mesolimbic dopamine system. Behavioral and neurochemical studies have shown that the cholinergic muscarinic M(4) receptor subtype plays an important role in regulation of dopaminergic neurotransmission.
Here we investigated for the first time the involvement of M(4) receptors in the reinforcing effects of cocaine using chronic intravenous cocaine self-administration in extensively backcrossed M(4) receptor knockout (M(4) (-/-)) mice.
We evaluated acquisition of cocaine self-administration in experimentally naïve mice. Both cocaine self-administration and food-maintained operant behavior were evaluated under fixed ratio 1 (FR 1) and progressive ratio (PR) schedules of reinforcement. In addition, cocaine-induced dopamine release and cocaine-induced hyperactivity were evaluated.
M(4) (-/-) mice earned significantly more cocaine reinforcers and reached higher breaking points than their wild-type littermates (M(4) (+/+)) at intermediate doses of cocaine under both FR 1 and PR schedules of reinforcement. Under the PR schedule, M(4) (-/-) mice exhibited significantly higher response rates at the lowest liquid food concentration. In accordance with these results, cocaine-induced dopamine efflux in the nucleus accumbens and hyperlocomotion were increased in M(4) (-/-) mice compared to M(4) (+/+) mice.
Our data suggest that M(4) receptors play an important role in regulation of the reward circuitry and may serve as a new target in the medical treatment of drug addiction.
[show abstract][hide abstract] ABSTRACT: A delicate balance exists between the central dopaminergic and cholinergic neurotransmitter systems with respect to motor function. An imbalance can result in motor dysfunction as observed in Parkinson's disease patients and in patients treated with antipsychotic compounds. Cholinergic receptor antagonists can alleviate extrapyramidal symptoms in Parkinson's disease and motor side effects induced by antipsychotics. The effects of anticholinergics are mediated by muscarinic receptors of which five subtypes (M(1)-M(5)) exist. Muscarinic M(4) receptors are found at high concentrations in motor parts of the striatum, suggesting a role for muscarinic M(4) receptors in the motor side effects of antipsychotics, and in the alleviation of these side effects by anticholinergics. Here we investigated the potential role of the muscarinic M(4) receptor in catalepsy induced by antipsychotics (haloperidol and risperidone) as well as the anti-cataleptic effects of the non-selective anticholinergic drug scopolamine in fully backcrossed muscarinic M(4) receptor knockout mice. The drug-induced catalepsy was strongly attenuated, but not abolished, in M(4) knockout mice as compared to wild-type controls. Scopolamine further attenuated the cataleptic response in M(4) knockout mice, suggesting that non-M(4) muscarinic receptors also participate in the anti-cataleptic effects. In conclusion, these data indicate an important role for M(4) receptors in antipsychotic-induced motor side effects and suggest that M(4) receptors could be a target for future pharmacological treatment of antipsychotic-induced as well as idiopathic parkinsonism.
European journal of pharmacology 01/2011; 656(1-3):39-44. · 2.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: Muscarinic M(5) receptors are the only muscarinic receptor subtype expressed by dopamine-containing neurons of the ventral tegmental area. These cells play an important role for the reinforcing properties of psychostimulants and M(5) receptors modulate their activity. Previous studies showed that M(5) receptor knockout (M (5) (-/-) ) mice are less sensitive to the reinforcing properties of addictive drugs.
Here, we investigate the role of M(5) receptors in the effects of amphetamine and cocaine on locomotor activity, locomotor sensitization, and dopamine release using M (5) (-/-) mice backcrossed to the C57BL/6NTac strain.
Sensitization of the locomotor response is considered a model for chronic adaptations to repeated substance exposure, which might be related to drug craving and relapse. The effects of amphetamine on locomotor activity and locomotor sensitization were enhanced in M (5) (-/-) mice, while the effects of cocaine were similar in M (5) (-/-) and wild-type mice.
Consistent with the behavioral results, amphetamine-, but not cocaine, -elicited dopamine release in nucleus accumbens was enhanced in M (5) (-/-) mice.
The different effects of amphetamine and cocaine in M (5) (-/-) mice may be due to the divergent pharmacological profile of the two drugs, where amphetamine, but not cocaine, is able to release intracellular stores of dopamine. In conclusion, we show here for the first time that amphetamine-induced hyperactivity and dopamine release as well as amphetamine sensitization are enhanced in mice lacking the M(5) receptor. These results support the concept that the M(5) receptor modulates effects of addictive drugs.